Faculty Bibliography

Background: Synthetic cannabinoid receptor agonists (SCRAs) are heterogeneous compounds developed as probes of the endogenous cannabinoid system or potential therapeutic agents, which clandestine laboratories subsequently synthesize and market as abusable designer drugs. Objectives: We assessed clinical toxicity associated with SCRA overdose, and hypothesized associations with agitation and cardiotoxicity. Methods: This subgroup analysis of a large drug overdose cohort study involved consecutive ED patients at two large urban teaching hospitals collected between 2009-13. Clinical characteristics of patients with exposure to SCRAs (SRCA subgroup) were compared with patients who smoked regular marijuana (MJ subgroup). Data included demographics, exposure details, vital signs, mental status, and basic chemistries gathered as part of routine clinical care. Study outcomes included altered mental status (agitation, GCS), and cardiotoxicity (myocardial injury, dysrhythmia). Dysrhythmia was defined as ventricular tachycardia or fibrillation. Assuming 30% prevalence of the predictor and outcome, we calculated the need to enroll 84 patients to show 3.5-fold relative risk with 80% power and 5% alpha. Results: 89 patients reported exposure to any cannabinoid, of whom 17 reported SCRAs (17 SCRA, 72 MJ, mean age 38.7, 78% males). There were no significant differences between SRCA and MJ with respect to demographics (age, sex, race), exposure history (suicidality, misuse, intent), or vital signs. Laboratory variables associated with SCRA were lower mean bicarbonate (p<0.05) and elevated mean serum glucose (p<0.05). Mental status agitation was significantly more likely in SCRA subgroup (OR 3.3, CI 1.1-9.6). Cardiotoxicity was more pronounced in SCRA subgroup (dysrhythmia OR 9.8, CI 1.0-116). Conclusion: Clinical toxicity of SCRA overdose was much more severe than MJ, including metabolic abnormalities, neurotoxicity and cardiotoxicity. Future studies should assess optimal treatment modalities to prevent adverse clinical outcomes

Background: In the US, deaths from prescription opioids exceed deaths from all illicit drugs combined. Objectives: We aimed to derive risk factors for severe respiratory depression (SRD) and mortality in ED patients with prescription opioid overdose. Methods: This secondary data analysis used data from a prospective cohort of acute drug overdose patients at 2 urban teaching hospitals from 2009-13. We analyzed the subgroup with prescription opioids overdose with these exclusion criteria: age <18, alternate diagnoses, lacking data. The following data was extracted: demographics, initial vital signs, blood gas, ED endotracheal intubation (ETI), naloxone administration, toxicology screen results and in-hospital mortality. The study outcome was SRD defined by either (a) naloxone administration or (b) ETI. Assuming a 20% prevalence of SRD and predictors, we calculated the need to analyze 300 patients to demonstrate 3-fold risk difference with 80% power and 5% alpha. (Table presented) Results: 354 patients were screened, of whom 47 were excluded, leaving 307 patients for analysis (mean age 44.7, 42% females, 2.0% mortality). Prescription opioid overdoses involved the following: oxycodone, 124; methadone, 116; hydrocodone, 31; codeine, 27; morphine, 12; tramadol, 12; buprenorphine, 7; fentanyl, 4; oxymorphone, 3; tapentadol, 2 (some patients exposed to >1). 109 patients met criteria for SRD (90 naloxone alone, 9 ETI alone, 10 both). Mean age was higher in the SRD group (51.1 vs. 41.1, p<0.001), and suicidality was inversely correlated with SRD (OR 0.29, CI 0.17-0.5), while gender had no correlation (p=0.95). Risk for SRD was highly dependent on the type of prescription opioid (see Table 783). In 6 deaths, mortality was associated with tachycardia (p<0.001), hyperlactatemia (p<0.05), and hypotension (p<0.01). Conclusion: In this cohort of patients with prescription opioid overdose, we derived clinical risk factors for SRD (age and specific opioid drugs) as well as mortality (vital sign abnormalities and hyperlactatemia)

OBJECTIVES: It was recently demonstrated that adverse cardiovascular events (ACVE) complicate a high proportion of hospitalizations for patients with acute drug overdoses. The aim of this study was to derive independent clinical risk factors for ACVE in patients with acute drug overdoses. METHODS: This prospective cohort study was conducted over 3 years at two urban university hospitals. Patients were adults with acute drug overdoses enrolled from the ED. In-hospital ACVE was defined as any of myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest. RESULTS: There were 1,562 patients meeting inclusion/exclusion criteria (mean age, 41.8 years; female, 46%; suicidal, 38%). ACVE occurred in 82 (5.7%) patients (myocardial injury, 61; shock, 37; dysrhythmia, 23; cardiac arrests, 22) and there were 18 (1.2%) deaths. On univariate analysis, ACVE risk increased with age, lower serum bicarbonate, prolonged QTc interval, prior cardiac disease, and altered mental status. In a multivariable model adjusting for these factors as well as patient sex and hospital site, independent predictors were: QTc > 500 msec (3.8% prevalence, odds ratio [OR] = 27.6), bicarbonate < 20 mEq/L (5.4% prevalence, OR = 4.4), and prior cardiac disease (7.1% prevalence, OR = 9.5). The derived prediction rule had 51.6% sensitivity, 93.7% specificity, and 97.1% negative predictive value, while presence of two or more risk factors had 90.9% positive predictive value. CONCLUSIONS: The authors derived independent clinical risk factors for ACVE in patients with acute drug overdose, which should be validated in future studies as a prediction rule in distinct patient populations and clinical settings.

BACKGROUND: The Extracorporeal Treatments in Poisoning workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTRs) in poisoning. Here, the workgroup presents its systematic review and recommendations for theophylline. METHODS: After a systematic review of the literature, a subgroup reviewed articles, extracted data, summarized findings, and proposed structured voting statements following a pre-determined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Anonymous votes were compiled, returned, and discussed. A second vote determined the final recommendations. RESULTS: 141 articles were included: 6 in vitro studies, 4 animal studies, 101 case reports/case series, 7 descriptive cohorts, 4 observational studies, and 19 pharmacokinetic studies, yielding a low-to-very-low quality of evidence for all recommendations. Data on 143 patients were reviewed, including 10 deaths. The workgroup concluded that theophylline is dialyzable (level of evidence = A) and made the following recommendations: ECTR is recommended in severe theophylline poisoning (1C). Specific recommendations for ECTR include a theophylline concentration [theophylline] > 100 mg/L (555 mumol/L) in acute exposure (1C), the presence of seizures (1D), life-threatening dysrhythmias (1D) or shock (1D), a rising [theophylline] despite optimal therapy (1D), and clinical deterioration despite optimal care (1D). In chronic poisoning, ECTR is suggested if [theophylline] > 60 mg/L (333 mumol/L) (2D) or if the [theophylline] > 50 mg/L (278 mumol/L) and the patient is either less than 6 months of age or older than 60 years of age (2D). ECTR is also suggested if gastrointestinal decontamination cannot be administered (2D). ECTR should be continued until clinical improvement is apparent or the [theophylline] is < 15 mg/L (83 mumol/L) (1D). Following the cessation of ECTR, patients should be closely monitored. Intermittent hemodialysis is the preferred method of ECTR (1C). If intermittent hemodialysis is unavailable, hemoperfusion (1C) or continuous renal replacement therapies may be considered (3D). Exchange transfusion is an adequate alternative to hemodialysis in neonates (2D). Multi-dose activated charcoal should be continued during ECTR (1D). CONCLUSION: Theophylline poisoning is amenable to ECTRs. The workgroup recommended extracorporeal removal in the case of severe theophylline poisoning.

STUDY OBJECTIVE: Calcium channel blocker poisonings account for a substantial number of reported deaths from cardiovascular drugs. Although supportive care is the mainstay of treatment, experimental therapies such as high-dose insulin-euglycemia and lipid emulsion have been studied in animal models and used in humans. In the most severe cases, even aggressive care is inadequate and deaths occur. In both experimental models and clinical cases of vasodilatory shock, methylene blue improves hemodynamic measures. It acts as a nitric oxide scavenger and inhibits guanylate cyclase that is responsible for the production of cyclic guanosine monophosphate (cGMP). Excessive cGMP production is associated with refractory vasodilatory shock in sepsis and anaphylaxis. The aim of this study is to determine the efficacy of methylene blue in an animal model of amlodipine-induced shock. METHODS: Sprague-Dawley rats were anesthetized, ventilated, and instrumented for continuous blood pressure and pulse rate monitoring. The dose of amlodipine that produced death within 60 minutes was 17 mg/kg per hour (LD50). Rats were divided into 2 groups: amlodipine followed by methylene blue or amlodipine followed by normal saline solution, with 15 rats in each group. Rats received methylene blue at 2 mg/kg during 5 minutes or an equivalent amount of normal saline solution in 3 intervals from the start of the protocol: minutes 5, 30, and 60. The animals were observed for a total of 2 hours after the start of the protocol. Mortality risk and survival time were analyzed with Fisher's exact test and Kaplan-Meier survival analysis with the log rank test. RESULTS: Overall, 1 of 15 rats (7%) in the saline solution-treated group survived to 120 minutes compared with 5 of 15 (33%) in the methylene blue-treated group (difference -26%; 95% confidence interval [CI] -54% to 0.3%). The median survival time for the normal saline solution group was 42 minutes (95% CI 28.1 to 55.9 minutes); for the methylene blue group, 109 minutes (95% CI 93.9 to 124.1 minutes). Pulse rate and mean arterial pressure (MAP) differences between groups were analyzed until 60 minutes. Pulse rate was significantly higher in the methylene blue-treated group beginning 25 minutes after the start of the amlodipine infusion (95% CI 30 to 113 minutes) that was analyzed until 60 minutes. MAP was significantly higher in the methylene blue-treated group starting 25 minutes after the amlodipine infusion (95% CI 2 to 30 minutes) that was analyzed until 60 minutes. CONCLUSION: Methylene blue did not result in a significant difference in mortality risk. There was an increased pulse rate, MAP, and median survival time in the methylene blue group.

Abstract Context. The extent of non-absorbed drug burden in the GI tract following overdose is unknown. Patients who present with clinical signs of toxicity may not undergo decontamination due to assumption that the drug has already been completely absorbed and because of limited scientific evidence of benefit for routine GI decontamination in poisoned patients. Objective. The goal of this study was to assess whether people who die of an oral overdose have unabsorbed drug present in the GI tract. The secondary goal was to analyze pharmacologic characteristics of retained drugs when present. Materials and methods. Retrospective review of autopsy reports from 2008 to 2010, whose cause of death was determined as "intoxication" or "overdose, was performed at the Office of Chief Medical Examiner of the City of New York (OCME NYC)." Decedents of all ages were identified via electronic OCME database. Inclusion criteria were as follows: 1) cause of death "intoxication" or "overdose" noted by forensic autopsy, 2) ingestion of a solid drug formulation. Results. 92 out of 1038 autopsies (9%) that met inclusion criteria had documentation of retained pill fragments, granules, paste, sludge, slurry, or whole pills in the GI tract. The most common drugs found were opioids and anticholinergics. Ninety-eight percent (98%) of the retained drugs were either modified-release preparations or drugs known to slow GI transit. Most decedents were dead on arrival; there were twelve in-hospital deaths and eleven patients died in the Emergency Department. Bupropion and venlafaxine were responsible for four deaths in those who received medical care. One person died in the ICU following bupropion ingestion. Discussion and conclusion. Overdose of an oral drug that either has modified-release properties or slows GI tract motility may result in substantial unabsorbed drug burden remaining in the GI tract.

Abstract Context. The optimal method of cooling hyperthermic patients is controversial. Although controlled data support ice water submersion, many authorities recommend a mist and fan technique. We report two patients with drug-induced hyperthermia, to demonstrate the rapid cooling rates of ice water submersion. Case details. Case 1. A 27-year-old man presented with a sympathomimetic toxic syndrome and a core temperature of 41.4 degrees C after ingesting 4-fluoroamphetamine. He was submerged in ice water and his core temperature fell to 38 degrees C within 18 minutes (a mean cooling rate of 0.18 degrees C/min). His vital signs stabilized, his mental status improved and he left on hospital day 2. Case 2. A 32-year-old man with a sympathomimetic toxic syndrome after cocaine use was transported in a body bag and arrived with a core temperature of 44.4 degrees C. He was intubated, sedated with IV benzodiazepines, and submerged in ice water. After 20 mins his temperature fell to 38.8 degrees C (a cooling rate of 0.28 degrees C/min). He was extubated the following day, and discharged on day 10. Discussion. In these two cases, cooling rates exceeded those reported for mist and fan technique. Since the priority in hyperthermia is rapid cooling, clinical data need to be collected to reaffirm the optimal approach.